Aldol Reactions of Conformationally Stable Axially Chiral Thiohydantoin Derivatives.

Two novel axially chiral -trifluoromethylphenyl thiohydantoin derivatives have been prepared atroposelectively from the reaction of and alanine methyl ester HCl salts with -trifluoromethylphenyl isothiocyanate in the presence of triethyl amine. It was found that after purification of the crude product by simple recrystallization, the amino acid esters yielded thiohydantoins having solely axial chirality whereas the ones returned the isomers only. This result prompted us to perform sterically controlled aldol reactions on and thiohydantoin atropisomers. It was found that during the aldol reaction of 3--trifluoromethyl-5-methylthiohydantoins, the -trifluoromethyl group of the isomers efficiently shielded the face of the intermediate and in this way, enabled the selective formation of only the configured aldol products at C5 of the heterocyclic ring. The thiohydantoins, on the other hand, yielded only the C5 configured aldol products as a result of the face shielding of the -trifluoromethyl group of intermediate enolates. A noteworthy face selectivity of the benzaldehyde molecule was not observed ( only 3/2) during the aldolization of trifluoromethylphenyl derivatives of thiohydantoins. Aldol reactions were also done using the previously synthesized axially chiral thiohydantoins with -Cl, Br, and I phenyl substituents which had predominantly conformations (/ ratios > 95%), and the stereochemical outcomes were compared with those of the -trifluoromethyl substituted ones. 80-90% face selectivity of the benzaldehyde molecule was observed for the axially chiral -halophenyl substituted thiohydantoins. The syntheses done with axially chiral 3--trifluoromethylphenyl- and 3--iodophenyl-5-methyl thiohydantoins enabled stereoselective formation of quaternized chiral carbon centers at C5 of the thiohydantoin ring.